WO2005025496B1 - Aliphatic pyrazinoylguanidine sodium channel blockers - Google Patents

Aliphatic pyrazinoylguanidine sodium channel blockers

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Publication number
WO2005025496B1
WO2005025496B1 PCT/US2004/026808 US2004026808W WO2005025496B1 WO 2005025496 B1 WO2005025496 B1 WO 2005025496B1 US 2004026808 W US2004026808 W US 2004026808W WO 2005025496 B1 WO2005025496 B1 WO 2005025496B1
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Prior art keywords
ch
compound
nr
chor
nh
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PCT/US2004/026808
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French (fr)
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WO2005025496A2 (en )
WO2005025496A3 (en )
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Michael R Johnson
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Parion Sciences Inc
Michael R Johnson
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C07D241/28Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
    • C07D241/30Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms in which said hetero—bound carbon atoms are part of a substructure —C(=X)—X—C(=X)—X— in which X is an oxygen or sulfur atom or an imino radical, e.g. imidoylguanidines
    • C07D241/34(Amino-pyrazine carbonamido) guanidines [2,5]

Abstract

The present invention relates to sodium channel blockers. The present invention also includes a variety of methods of treatment using these inventive sodium channel blockers.

Claims

AMENDED CLAIMS [received by the International Bureau on 15 June 2005 (15.06.2005); original claims 1-178 replaced by amended claims 1-179 (30 pages)]
1. A compound represented by formula (I):
Figure imgf000002_0001
wherein X is hydrogen, halogen, trifluoromethyl, lower alkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl; Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen, lower alkyl, unsubstituted or substituted mononuclear aryl, or -N(R )2; R1 is hydrogen or lower alkyl; each R2 is, independently, -R7, -(CH2)m-OR8, -(CH2)m-NR7R10, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -(CH2CH2O)m-R8,
-(CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R,0, -(CH2)n-Zg-R7,-(CH2)m-NR10- CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-CO2R7, or
Figure imgf000002_0002
R3 and R4 are each, independently, hydrogen, a group represented by formula (A), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-lower alkyl, (halophenyl)-lower alkyl, lower-(alkylphenyl alkyl), lower (alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl- lower alkyl, with the proviso that at least one of R3 and R4 is a group represented by formula (A):
— (C(RL)2)O-X-(C(RL)2)P-CR5R6R6 (A) each RL is, independently, -R7, -(CH2)n-OR8, -O-(CH2)m-OR8, -(CH2)n-NR7R10, -O- (CH2)m-NR7R' °, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m(CHOR8)(CHOR8)π- CH2OR8, -(CH2CH2O)m-R8, -O-(CH2CH2O)m-R8, -(CH2CH2O)m-CH2CH2NR7R10, -O- (CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R10, -O-(CH2)m-C(=O)NR7R10, -(CH2)n- (Z)g-R7, -O-(CH2)m-(Z)g-R7, -(CH2)n-NR,0-CH2(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m- NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-CO2R7, -O-(CH2)m-CO2R7, -OSO3H, -O- glucuronide, -O-glucose,
Figure imgf000003_0001
each o is, independently, an integer from 0 to 17; each p is an integer from 0 to 17; with the proviso that the sum of o and p in each contiguous chain is from 1 to 17; each x is, independently, -O-, -NR10-, -C(=O)-, -CHOH-, -C(=N-R10)-, -CHNR7R10-, or represents a single bond, with the proviso that when x is a single bond the sum of o and p is from 7 to 17; each R5 is, independently, -O-(CH2)m-OR8, -(CH2)n-NR7R10, -O-(CH2)m-NR7R10, - (CH2)n(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, -(CH2CH2O)m- R8, -O-(CH2CH2O)m-R8, -(CH2CH2O)m-CH2CH2NR7R10, -O-(CH2CH2O)m-CH2CH2NR7R10, ■ (CH2)n-C(=O)NR7R10, -O-(CH2)m-C(=O)NR7R10, -(CH2)n-(Z)g-R7, -O-(CH2)m-(Z)g-R7, - (CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n- CH2OR8, -(CH2)n-CO2R7, -O-(CH2)m-CO2R7, -OSO3H, -O-glucuronide, -O-glucose,
Figure imgf000003_0002
107 -(CH2)n-NR12R12, -O-(CH2)m-NR12R12, -O-(CH2)n-NR12R12, -O-(CH2)m-(Z)gR12, - (CH2)nNRuRπ, -O-(CH2)mNRuRn, -(CH2)n-N®-(Rn)3, -O-(CH2)m-N®-(Rπ)3, -(CH2)n-(Z)g- (CH2)m-NR10R10, -O-(CH2)Itl-(Z)g-(CH2)m-NR10R10, -(CH2CH2O)m-CH2CH2NR12R12, -O- (CH2CH2O)m-CH2CH2NR12R,2, -(CH2)n-(C-O)NR12R12, -O-(CH2)m-(C=O)NR12R,2,-O- (CH2)m-(CHOR8)mCH2NR10-(Z)g-R10, -(CH2)n-(CHOR8)mCH2-NR10-(Z)g-R10, -(CH2)nNR10- O(CH2)m(CHOR8)nCH2NR,0-(Z)g-R,0, -O(CH2)m-NR10-(CH2)-(CHOR8)nCH2NR10-(Z)g-R,(), -(Het)-(CH2)m-OR8, -(Het)-(CH2)m-NR7R10, -(Het)-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, - (Het)-(CH2CH2O)m-R8, -(Het)-(CH2CH2O)m-CH2CH2NR7R10, -(Het)-(CH2)m-C(=O)NR7R10,- (Het)-(CH2)m-(Z)g-R7, -(Het)-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(Het)-(CH2)m- CO2R7, -(Het)-(CH2)m-NR12R, 2, -(Het)-(CH2)n-NR,2R12, -(Het)-(CH2)m-(Z)gR12, -(Het)-
(CH2)mNRnR", -(Het)-(CH2)m-N®-(Rn)3, -(Het)-(CH2)m-(Z)g-(CH2)m-NRl0R10, -(Het)- (CH2CH2O)m-CH2CH2NR12R12, -(Het)-(CH2)m-(C=O)NR12R12, -(Het)-(CH2)m- (CHOR8)mCH2NR10-(Z)g-R10, -(Het)-(CH2)m-NR,0-(CH2)m-(CHOR8)nCH2NR10-(Z)g-R10, -(CH2)n(CHOR8)(CHOR8-7-CH2OR8, with the proviso that at least two -CH2OR8 are located
1,2- or 1,3- to each other and the R groups are joined to form a cyclic mono- or di- substituted 1,3-dioxane or 1,3-dioxolane, -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located 1,2- or 1,3- to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane, -(CH2)n-NR10- CH2(CHOR8)(CHOR8-7-CH2OR8, with the proviso that at least two -CH2OR8 are located 1,2- or 1,3- to each other and the R8 groups are joined to form a cyclic mono- or di- substituted 1,3-dioxane or 1,3-dioxolane, -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR are located 1,2- or 1,3- to each other and the R groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane, - Link-(CH2)n-CAP, -Link-(CH2)n(CHOR8)(CHOR8)n-CAP, -Link-(CH2CH2θ)m-CH2-CAP, - Link-(CH2CH2O)m-CH2CH2-CAP, -Link-(CH2)n-(Z)g-CAP, -Link-(CH2)n(Z)g-(CH2)m-CAP, - Link-(CH2)n-NR, 3-CH2(CHOR8)(CHOR8)n-CAP, -Link-(CH2)n-(CHOR8)mCH2-NR13-(Z)g- C AP, -Link-(CH2)nNR' 3-(CH2)m(CHOR8)nCH2NR' 3-(Z)g-CAP, -Link-(CH2)m-(Z)g-(CH2)m- CAP, -Link-NH-C(=O)-NH-(CH2)m-CAP, -Link-(CH2)m-C(=O)NR13-(CH2)m- C(=O)NRIOR10, -Link-(CH2)m-C(=O)NR,3-(CH2)m-CAP, -Link-(CH2)m-C(=O)NRnRu, - Link-(CH2)m-C(=O)NR12R12, -Link-(CH2) n-(Z)g-(CH2)m-(Z)g-CAP, or -Link-Zg-(CH2)m- Het-(CH2)m-CAP;
108 each Link is, independently, -O-, -(CH2)n-, -O(CH2)m-, -NR13-C(=O)-NR13, -NR13- C(=O)-(CH2)m-, -C(=O)NR,3-(CH2)m, -(CH2)n-Zg-(CH2)n, -S-,-SO-, -SO2-, -SO2NR7-, -SO2NR10-, or -Het-; each CAP is, independently, thiazolidinedione, oxazolidinedione, -heteroaryl-C(=O)N R13 R13, -heteroaryl-W, -CN, -O-C(=S)NR13 R13, -ZgR13, -CR10(ZgR!3)(ZgR13), -C(=O)OAr, -C(=O)N R13Ar, imidazoline, tetrazole, tetrazole amide, -SO2NHR13, -SO2NH-C(R13R13)- (Z)g-R13, a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
Figure imgf000005_0001
each Ar is, independently, phenyl, substituted phenyl, wherein the substituents of the substituted phenyl are 1-3 substituents independently selected from the group consisting of OH, OCH3, NR13R13, Cl, F, and CH3, or heteroaryl; each W is independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(=O)N R13 R13, -CN, -O-C(=S)NR13 R13, -ZgR13, -CR10(ZgR13)(ZgR13), -C(=O)OAr, -C(=O)N R13Ar, imidazoline, tetrazole, tetrazole amide, -SO2NHR13, -SO2NH-C(R13R13)-(Z)g-R13, a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
Figure imgf000005_0002
each R6 is, independently, -R5, -R7, -OR8, -N(R7)2, -(CH2)m-OR8, -O-(CH2)m-OR8, -(CH2)n-NR7R10, -O-(CH2)m-NR7R10,
-(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, -(CH2CH2O)m-R8, -O-(CH2CH2O)m-R8, -(CH2CH2O)m-CH2CH2NR7R10, -O-(CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R10, -O-(CH2)m-C(=O)NR7R10, -(CH2)n-(Z)g-R7, -O-(CH2)m-(Z)g-R7, -(CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8,
109 -(CH2)n-CO2R7, -O-(CH2)m-CO2R7, -OSO3H, -O-glucuronide, -O-glucose,
Figure imgf000006_0001
each R7 is, independently, hydrogen lower alkyl, phenyl, substituted phenyl, or CH2(CHOR)8 m-R10; each R is, independently, hydrogen, lower alkyl, -C(=O)-R , glucuronide, 2- tetrahydropyranyl, or
Figure imgf000006_0002
each R9 is, independently, -CO2R , -CON(R1 )2, -SO2CH2R13, or -C(=O)R13; each R10 is, independently, -H, -SO2CH3, -CO2R13, -C(=O)NR13R13,
-C(=O)R13, or -(CH2) m-(CHOH)n-CH2OH; each Z is, independently, -CHOH, -C(=O), -(CH2)n-, -CHNR1JR , C=NR' or -NR13; each R1 ' is, independently, lower alkyl; each R12 is, independently, -SO2CH3, -CO2R13, -C(=O)NR13R13, -C(=O)R13, or -CH2- (CHOH)n-CH2OH; each R13 is, independently, -R7 or -R10; each Het is independently, -NR13-, -S-, -SO-, -SO2-, -O-, -SO2NR13-, -NHSO2-, -NR13CO-, or -CONR13-; each g is, independently, an integer from 1 to 6; each m is, independently, an integer from 1 to 7; each n is, independently, an integer from 0 to 7;
110 with the proviso that, when any two -CH2OR groups in the compound are located ,2- or 1,3- with respect to each other, the R8 groups may be joined to form a cyclic mono- or i-substituted 1,3-dioxane or 1,3-dioxolane; or a pharmaceutically acceptable salt thereof, and inclusive of all enantiomers, diastereomers, and racemic mixtures thereof.
2. The compound of Claim 1, wherein Y is -NH2.
3. The compound of Claim 2, wherein R2 is hydrogen.
4. The compound of Claim 3, wherein R1 is hydrogen.
5. The compound of Claim 4, wherein X is chlorine.
The compound of Claim 5, wherein R3 is hydrogen.
7. The compound of Claim 6, wherein each RL is hydrogen.
8. The compound of Claim 7, wherein o is 4.
9. The compound of Claim 8, wherein p is 3.
10. The compound of Claim 9, wherein x represents a single bond.
11. The compound of Claim 10, wherein each R6 is hydrogen.
12. The compound of Claim 11, wherein R5 is -O-(CH2)m-OR8.
13. The compound of Claim 11 , wherein R5 is -O-(CH2)4-OH.
14. The compound of Claim 1, which is represented by the formula:
111
Figure imgf000008_0001
15. The compound of Claim 11 where in R 5D i •s -O(CH2)3-OH
16. The compound of Claim 1 , which is represented by the formula:
Figure imgf000008_0002
17. The compound of Claim 11 , wherein R5 is -(CH2)n-NR7R10, -NHSO2CH3, - CH2NH(C=O)-(OCH3)3, -NH(C=O)CH3, -CH2NH2, -NH-CO2C2H5, -NH-CO2C2H5, -NH- CO2C2H5, -CH2NH(C=O)CH3, -CH2NHCO2CH3, -CH2NHSO2CH3, -(CH2)4- NH(C=O)O(CH3)3, -(CH2)4-NH2, -(CH2)3-NH(C=O)O(CH3)3, or -(CH2)3-NH2.
18. The compound of Claim 1 , which is represented by the formula:
Figure imgf000008_0003
19. The compound of Claim 11 , wherein R5 is -O-(CH2)m-NR7R10, - OCH2CH2NHCO2(CH3)3, -OCH2CH2NHCO2C2H5, -O-(CH2)3-NH-CO2-(CH3)3, -O(CH2)3- NH2, -OCH2CH2NHSO2CH3, or -O-CH2CH2NH2
20. The compound of Claim 1 , which is represented by the formula:
Figure imgf000008_0004
112
21. The compound of Claim 11 , wherein R5 is -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, -OCH2CHOHCH2O-glucuronide, -
OCH2CH2CHOHCH2OH, -OCH2-(θ(-CHOH)2CH2OH, or -OCH2-(CHOH)2CH2OH.
22. The compound of Claim 1, which is represented by the formula:
Figure imgf000009_0001
23. The methanesulfonic acid salt of the compound of Claim 22.
24. The compound of Claim 1, which is represented by the formula:
Figure imgf000009_0002
25. The compound of Claim 1 , which is represented by the formula:
OCH2-(alphaCHOH)CH2OH
Figure imgf000009_0003
26. The compound of Claim 1, which is represented by the formula:
Figure imgf000009_0004
27. The compound of Claim 11 , wherein R5 is -(CH2CH2O)m-R8 or -O-(CH2CH2O)m-R8.
113
28. The compound of Claim 1 , which is represented by the formula:
Figure imgf000010_0001
29. The compound of Claim 1, which is represented by the formula:
Figure imgf000010_0002
30. The compound of Claim 1, which is represented by the formula:
Figure imgf000010_0003
31. The compound of Claim 11 , wherein R5 is -(CH2CH2O)m-CH2CH2NR7R1 °, -O- (CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R10, or -C(=O)NH2.
32. The compound of Claim 11 , wherein R5 is -O-(CH2)m-C(=O)NR7R10, -O-CH2- (C=O)NHCH2CHOH, -O-CH2-(C=O)NHCH2CHOHCH2OH, -O-CH2(C=O)NHCH2(CHOH)2CH2OH, -O-CH2C(C=O)NHSO2CH3, -O- CH2(C=O)NHCO2CH3, -O-CH2-C(C=O)NH-C(C=O)NH2, or -O-CH2-(C=O)NH- (C=O)CH3.
33. The compound of Claim 11 , wherein R5 is -(CH2)n-(Z)g-R7, (CH2)n-(C=N)-NH2, -(C=NH)NH2, (CH2)n-NH-C(=NH)-NH2, -(CH2)3-NH-C(=NH)-NH2, -CH2NH-C(=NH)-NH2, or (CH2)n-CONHCH2(CHOH)n-CH2OH.
34. The compound of Claim 1, which is represented by the formula:
114
Figure imgf000011_0001
35. The compound of Claim 11, wherein R5 is NH-C(=O)-CH2-(CHOH)nCH2OH, NH-(C=O)-NH-CH2(CHOH)2CHOH, or -NHC(C=O)NHCH2CH2OH.
36. The compound of Claim 1, which is represented by the formula:
Figure imgf000011_0002
37. The compound of Claim 11, wherein R5 is -O-(CH2)m-(Z)g-R7, -O-(CH2)m-NH- C(=NH)-N(R7)2, -O(CH2)3-NH-C(=NH)-NH2, or -O-(CH2)m-CHNH2-CO2NR7R10.
38. The compound of Claim 1 , which is represented by the formula:
Figure imgf000011_0003
39. The compound of Claim 11 , wherein R5 is -OCH2-CHNH2-CO2NH2.
40. The (R) enantiomer of the compound of Claim 37.
41. The wherein (S) enantiomer of the compound of Claim 37.
42. The compound of Claim 1, which is represented by the formula:
Figure imgf000011_0004
43. The compound of Claim 11 , wherein R5 is -OCH2CHOH-CH2NHCO2(CH3)3.
115
44. The compound of Claim 1, which is represented by the formula:
Figure imgf000012_0001
45. The compound of Claim 11 wherein R5 is -(CH2)n-NR - CH2(CHOR8)(CHOR8)n-CH2OR8.
46. The compound of Claim 11 , wherein R5 is -NHCH2(CHOH)2CH2OH.
47. The compound of Claim 11 , wherein R5 is -O-(CH2)m-NR10- CH2(CHOR8)(CHOR8)n-CH2OR8 -O-(CH2)m-NH-erythritol, -O-(CH2)m-NH-sorbitol, -O- (CH2)m-NH-ertyhritol, -O-(CH2)m-NH-xylitol, or -O-(CH2)m-NH-glycidol.
48. The compound of Claim 11 , wherein R5 is -O-(CH2)m-CO2R7, -OCH2CH2CO2(CH3)3, -OCH2CO2H, -OCH2CO2C2H5 , -OSO3H, -O-glucuronide, -O- glucose, or -O-CH2-dioxolane.
49. The compound of Claim 1 , wherein X is halogen; Y is -N(R7)2; R1 is hydrogen or C]-C3 alkyl; R2 is -R7, -(CH2)m-OR8, or -(CH2)n-CO2R7; R is a group represented by formula (A); and R is hydrogen, a group represented by formula (A), or lower alkyl.
50. The compound of Claim 1, wherein X is chloro or bromo; Y is -N(R7)2; R2 is hydrogen or Cι-C alkyl; at most three R6 are other than hydrogen as defined above; and at most three RL are other than hydrogen as defined above.
51. The compound of Claim 50, wherein Y is -NH2.
52. The compound of Claim 51 , wherein R4 is hydrogen; at most one R is other than hydrogen as defined above; and at most two R6 are other than hydrogen as defined above.
53. The compound of Claim 1 , wherein R5 is -(CH2)m-OR8, -O-(CH )m-OR8 (CH2)n-NR7R10, or -O-(CH2)m-NR7R10.
54. The compound of Claim 1 , wherein R5 is -(CH2)n(CHOR8)(CHOR8)n-CH2OR8 or -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8.
55. The compound of Claim 1 , wherein R5 is -(CH2CH2O)m-R8, -O-(CH2CH2O)m- R8, -(CH2CH2O)m-CH2CH2NR7R10, or -O-(CH2CH2O)m-CH2CH2NR7R10.
56. The compound of Claim 1 , wherein R5 is -(CH2)n-C(=O)NR7R10 or -O-(CH2)m- C(=O)NR7R10.
57. The compound of Claim 1 , wherein R5 is -(CH2)n-(Z)g-R7 or -O-(CH2)m-(Z)g-R7.
58. The compound of Claim 1 , wherein R5 is -(CH2)n-NR' °- CH2(CHOR8)(CHOR8)n-CH2OR8 or -O-(CH2)m-NR10-CH2(CHOR8)CHOR8)n-CH2OR8.
59. The compound of Claim 1, wherein R5 is selected from the group consisting of -O-(CH2)3-OH, -NH2, -O-CH2-(CHOH)2-CH2OH -O-CH2-CHOH-CH2OH, -O-CH2CH2-O-tetrahydropyran-2-yl,-O-CH2CHOH-CH2-O-glucuronide, -O-CH2CH2OH, -O-(CH2CH2O)4-CH3, -O-CH2CH2OCH3, -O-CH2-(CHOC(=O)CH3)-CH2-OC(=O)CH3, -O-(CH2CH2O)2-CH3, -OCH2-CHOH-CHOH-CH2OH, -CH2OH, -CO2CH3,
117
Figure imgf000014_0001
and
Figure imgf000014_0002
60. The compound of Claim 1, wherein R5 is selected from the group consisting of - O-(CH2)3-OH, -NH2, -O-CH2-(CHOH)2-CH2OH, ortho -O-CH2-CHOH-CH2OH, meta -O- CH2-CHOH-CH2OH, -O-CH2CH2-O-tetrahydropyran-2-yl, -O-CH2CHOH-CH2-O- glucuronide, -O-CH2CH2OH, -O-(CH2CH2O)4-CH3, -O-CH2CH2OCH3, -O-CH2- (CHOC(=O)CH3)-CH2-OC(=O)CH3, -O-(CH2CH2O)2-CH3, -OCH2-CHOH-CHOH-CH2OH, -CH2OH, -CO2CH3, -SO3H, -O-glucuronide,
Figure imgf000014_0003
and
Figure imgf000014_0004
61. The compound of Claim 1 , wherein R is
118 -O-CH2CHOHCH2O-glucuronide, -OCH2CO2H,
-NHCH2(CHOH)2-CH2OH, -OCH2CO2Et, -NHSO2CH3, -O-CH2C(=O)NH2, -CH2NH2, -NHCO2Et,
-OCH2CH2CH2CH2OH, -CH2NHSO2CH3, -OCH2CH2CHOHCH2OH, -OCH2CH2NHCO2Et, -NH-C(=NH2)-NH2OHOH, -CH2CH-CH-CH2OH,
Figure imgf000015_0001
-O-CH2-CHOH-CH2-NHBoc, -OCH2CH2CH2NH2, -OCH2CH2NHCH2(CHOH)2CH2OH, -OCH2CH2NH(CH2[(CHOH)2CH2OH)]2, -(CH2)4-NHBoc, -(CH2)4-NH2, -(CH2)4-OH, -OCH2CH2NHSO2CH3, -(CH2)3-NH Boc, -(CH2)3NH2, or -O-CH2-CHOH-CH2-NH-C(=NH)-N(R7)2.
62. The compound of Claim 1, wherein
X is chloro or bromo;
Y is -N(R7)2;
R1 is hydrogen or C1-C3 alkyl;
R2 is hydrogen or C1-C3 alkyl;
R3 is a group represented by formula (A); and
R4 is hydrogen, a group represented by formula (A), or lower alkyl; 119 at most two R6 are other than hydrogen as defined above; and at most three RL are other than hydrogen as defined above;
63. The compound of Claim 62, wherein R4 is hydrogen; at most one RL is other than hydrogen as defined above; at most one R6 are other than hydrogen as defined above;
64. The compound of Claim 63, wherein X is chloro or bromo; Y is -N(R7)2; R1 is hydrogen or Cι-C3 alkyl; R2 is hydrogen or C1-C3 alkyl; R is a group represented by formula (A); and R4 is hydrogen, a group represented by formula (A), or lower alkyl; at most two R6 are other than hydrogen as defined above; and at most three R are other than hydrogen as defined above;
65. The compound of Claim 64, wherein R4 is hydrogen; and at most one R is other than hydrogen as defined above.
66. The compound of Claim 1 , wherein x is a single bond.
67. The compound of Claim 11, wherein R5 is -OCH2CH2OCH3, -(CH2)n-NR12R12, or -(CH2)n-N(SO2R7)2.
68. The compound of Claim 1, which is represented by the formula:
Figure imgf000016_0001
120
69. The compound of Claim 11, wherein R5 is -O-(CH2)m-NR12R12, -O-(CH2)m- NR12R12, -O-(CH2)m-N(SO2R7)2, -O-(CH2)m-(Z)gR12, -(CH2)n-CHNHBocCO2R7 (a), or -O- (CH2)m-CHNHBocCO2R7 ( ).
70. The compound of Claim 1, which is represented by the formula:
Figure imgf000017_0001
71. The compound of Claim 11, wherein R5 is -(CH2)n-N(R' ')2, -O-(CH2)m-N(R' ')2, -O-(CH2)2-N(Me)2, -(CH2)n-CHNH2CO2R7 (a), or -O-(CH2)m-CHNH2CO2R7 (a).
72. The compound of Claim 1, which is represented by the formula:
Figure imgf000017_0002
73. The compound of Claim 11, which is represented by the formula:
Figure imgf000017_0003
74. The compound of Claim 11 , wherein R5 is -O-(CH2)m-N+(R11)3.
75. The compound of Claim 1, which is represented by the formula:
Figure imgf000017_0004
121
76. The compound of Claim 11, wherein R5 is -(CH2)n-(Z)g-(CH2)m-NR10R10, - C(=O)NH-(CH2)m-N(R10)2, -NHC(=O)(CH2)m-N(R10)2, -C(-O)NH-(CH2)m-NH-C(=NH)- N(R7)2, or -NH-C(=O)-(CH2)mNH-C(=NH)-N(R10)2.
77. The compound of Claim 1, which is represented by the formula:
Figure imgf000018_0001
78. The compound of Claim 1, which is represented by the formula:
Figure imgf000018_0002
79. The compound of Claim 1 , which is represented by the formula:
Figure imgf000018_0003
80. The compound of Claim 11 , which is represented by the formula:
Figure imgf000018_0004
81. The compound of Claim 11 , wherein R5 is -O-(CH2)m-(CHOR8)mCH2NR10-(Z)g R10, -O-CH2-CHOH-CH2-guanadine, -(CH2)n-(CHOR8)mCH2-NR10-(Z)g-R10, -(CH2)nNR10- O(CH2)m(CHOR8)nCH2NR,0-(Z)g-R10, or -O(CH2)m-NR10-(CH2)m-(CHOH8)nCH2NR10-(Z)g- R10.
82. The compound of Claim 11 , wherein R5 is -(CH2CH2O)m-CH2CH2NR12R12, -O- (CH2CH2O)m-CH2CH2NR12R12, -(CH2)n-(C=O)NR12R12, or -O-(CH2)m-(C=O)NR12R12. 122
83. The compound of Claim 11, wherein R5 is -(Het)-(CH2)m-OR8, -(Het)-(CH2)m- NR7R10, -(Het)-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, -(Het)-(CH2CH2O)m-R8, -(Het)- (CH2CH2O)m-CH2CH2NR7R10, -(Het)-(CH2)m-C(=O)NR7R10, -(Het)-(CH2)m-(Z)g-R7, -(Het)- (CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(Het)-(CH2)m-CO2R7, -(Het)-(CH2)ni- NR12R12, -(Het)-(CH2)n-NR12R12, -(Het)-(CH2)m-(Z)gR12, -(Het)-(CH2)mNR11R11, -(Het)-
(CH2)m-N«-(Ru)3, -(Het)-(CH2)m-(Z)g-(CH2)m-NR10R10, -(Het)-(CH2CH2O)m- CH2CH2NR12R12, -(Het)-(CH2)m-(C=O)NR12R12, -(Het)-(CH2)m-(CHOR8)mCH2NRl0-(Z)g- R!0, or -(Het)-(CH2)m-NR10-(CH2)m-(CHOR8)nCH2NR10-(Z)g-R10.
84. The compound of Claim 11, wherein R5 is -(CH2)n(CHOR8)(CHOR8),-7- CH OR8, with the proviso that at least two -CH2OR8 are located 1,2- or 1,3- to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3- dioxolane.
85. The compound of Claim 11, wherein R5 is -(CH2)n-NR10- CH2(CHOR8)(CHOR8)!-7-CH2OR8, with the proviso that at least two -CH2OR8 are located 1,2- or 1,3- to each other and the R8 groups are joined to form a cyclic mono- or di- substituted 1,3-dioxane or 1,3-dioxolane.
86. The compound of Claim 11, wherein R5 is -O-(CH2)m-NR10- CH2(CHOR8)(CHOR8)n-CH2OR8, with the proviso that at least two -CH2OR8 are located adjacent to each other and the R groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane.
87. The compound of Claim 11 , wherein R5 is -O-(CH2)m(CHOR8)(CHOR8)n- CH2OR8, with the proviso that at least two -CH OR8 are located adjacent to each other and the R8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3- dioxolane.
88. The compound of Claim 1, which is represented by the formula:
123
Figure imgf000020_0001
89. The compound of Claim 1 , which is represented by the formula:
Figure imgf000020_0002
90. The compound of Claim 1, which is represented by the formula:
Figure imgf000020_0003
91. The compound of Claim 1 , which is represented by the formula:
Figure imgf000020_0004
92. The compound of Claim 1, which is represented by the formula:
Figure imgf000020_0005
124
93. The compound of claim 1, which is represented by the formula:
Figure imgf000021_0001
94. The compound of Claim 11 , wherein R5 is -Link-(CH2)n-CAP.
95. The compound of Claim 11, wherein R5 is -Link is -O- and CAP is thiazolidinedione.
96. The compound of Claim 1, which is represented by the formula:
Figure imgf000021_0002
97. The compound of Claim 11, wherein Link is -O- and CAP is tetrazole.
98. The compound of Claim 1, which is represented by the formula:
Figure imgf000021_0003
99. The compound of Claim 11, wherein Link is -O- and CAP is N,N-dimethyl sulfonamide.
100. The compound of Claim 1, which is represented by the formula:
Figure imgf000021_0004
125
101. The compound of Claim 1 , which is represented by the formula:
Figure imgf000022_0001
102. The compound of Claim 11, wherein Link is -O- and CAP is sulfonamide.
103. The compound of Claim 1, which is represented by the formula:
Figure imgf000022_0002
104. The compound of Claim 11 wherein Link is -O- and CAP is oxazolidinedione.
105. The compound of Claim 1, which is represented by the formula:
Figure imgf000022_0003
106. The compound of Claim 11 , wherein Link is -O- and CAP is -C(=O)N R10Ar
107. The compound of Claim 1, which is represented by the formula:
Figure imgf000022_0004
108. The compound of Claim 1, which is represented by the formula:
Figure imgf000022_0005
126
109. The compound of Claim 1 , which is represented by the formula:
Figure imgf000023_0001
110. The compound of claim 11, wherein Link is -O- and CAP is imidazole.
111. The compound of Claim 1 which is represented by the formula:
Figure imgf000023_0002
112. The compound of Claim 11 , wherein Link is -O- and CAP is cyano.
113. The compound of Claim 11 , which is represented by the formula:
Figure imgf000023_0003
114. The compound of Claim 11 , wherein CAP
Figure imgf000023_0004
115. The compound of Claim 1 , which is represented by the formula:
Figure imgf000023_0005
116. The compound of Claim 11 , wherein R5 is -Link-(CH2)n(CHOR8)(CHOR8)n- CAP, -Link-(CH2CH2O)m-CH2-CAP, -Link-(CH2CH2O)m-CH2CH2-CAP, -Link-(CH2)n-(Z)g- CAP, or -Link-(CH2)n(Z)g-(CH2)m-CAP.
127
117. The compound of Claim 1 , which is represented by the formula:
Figure imgf000024_0001
118. The compound of Claim 11 , wherein R5 is -Link-(CH2)n-NR1 °- CH2(CHOR8)(CHOR8)n-CAP, -Link-(CH2)n-(CHOR8)mCH2-NR10-(Z)g-CAP, or -Link- (CH2)nNR10-(CH2)m(CHOR8)nCH2NR10-(Z)g-CAP.
119. The compound of Claim 11 , wherein R5 is -Link-(CH2)m-(Z)g-(CH2)m-CAP, - Link-NH-C(=O)-NH-(CH2)m-C AP, -Link- CHz^-CC^NR1 °-(CH2)m-C(=O)NR1 °R10, -Link- (CH2)m-C(=O)NR10-(CH2)m-CAP, -Link-(CH2)m-C(=O)NR1 ,R11, -Link-(CH2)m- C(=O)NR12R12, or -Link-(CH2) π-(Z)g-(CH2)m-(Z)g-CAP.
120. The compound of Claim 1, wherein R5 is -Link-(CH2)n-CAP, -Link- (CH2)n(CHOR8)(CHOR8)n-CAP, -Link-(CH2CH2O)m-CH2-CAP, -Link-(CH2CH2O)m- CH2CH2-CAP, -Link-(CH2)n-(Z)g-CAP, -Link-(CH2)„(Z)g-(CH2)m-CAP, -Link-(CH2)n-NR10- CH2(CHOR8)(CHOR8)n-C AP, -Link-(CH2)n-(CHOR8)mCH2-NR' °-(Z)g-CAP, -Link- (CH2)nNR10-(CH2)m(CHOR8)nCH2NR10-(Z)g-CAP, -Link-(CH2)m-(Z)g-(CH2)m-CAP, -Link- NH-C(=O)-NH-(CH2)m-CAP, -Link-(CH2)m-C(=O)NR10-(CH2)m-C(=O)NR10R10, -Link- (CH2)m-C(=O)NR10-(CH2)m-CAP, -Link-(CH2)m-C(=O)NR' 'R1 ' , -Link-(CH2)m- C(=O)NR12R12, or -Link-(CH2)n-(Z)g-(CH2)m-(Z)g-CAP.
121. The compound of Claim 1 , which is represented by formula:
Figure imgf000024_0002
122. The compound of Claim 1, which is represented by formula:
Figure imgf000024_0003
128
123. The compound of Claim 1 , which is represented by formula:
Figure imgf000025_0001
124. The compound of Claim 1 , which is represented by formula:
Figure imgf000025_0002
125. The compound of Claim 1, which is represented by formula:
Figure imgf000025_0003
126. The compound of Claim 1 , which is represented by formula:
Figure imgf000025_0004
127. The compound of Claim 1 , which is represented by formula:
Figure imgf000025_0005
128. The compound of Claim 1 , which is represented by formula:
Figure imgf000025_0006
129. The compound of Claim 1 , which is represented by formula:
129
Figure imgf000026_0001
130. The compound of Claim 1, which is represented by formula:
Figure imgf000026_0002
132. The compound of Claim 1 , which is represented by formula:
Figure imgf000026_0003
133. The compound of Claim 1, which is represented by formula:
Figure imgf000026_0004
134. The compound of Claim 1 , which is represented by formula:
Figure imgf000026_0005
135. The compound of Claim 1 , which is represented by formula:
Figure imgf000026_0006
136. The compound of Claim 1, which is represented by formula:
Figure imgf000026_0007
130
137. The compound of Claim 1 , which is represented by formula:
Figure imgf000027_0001
138. The compound of Claim 1, which is represented by formula:
Figure imgf000027_0002
139. The compound of Claim 1, wherein x is a single bond.
140. The compound of Claim 1 , wherein the heteroaryl is a pyridyl, pyrazyl, tinazyl, furyl, furfuryl, thienyl, tetrazyl, thiazolidinedionyl and imidazoyl, pyrrolyl, furanyl, thiophenyl, quinolyl, indolyl, adenyl, pyrazolyl, thiazolyl, isoxazolyl, indolyl, benzimidazolyl, purinyl, quinolinyl, isoquinolinyl, pyridazyl, pyrimidyl, pyrazyl, 1,2,3- triazyl, 1,2,4-triazyl, 1,3, 5 -triazyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl or pterdyl.
141. The compound of Claim 1 , which is in the form of a pharmaceutically acceptable salt.
142. A composition, comprising: the compound of Claim 1; and a P2Y2 receptor agonist.
143. A composition, comprising: the compound of Claim 1 ; and a bronchodilator.
131
144. A pharmaceutical composition, comprising the compound of Claim 1 and a pharmaceutically acceptable carrier.
145. A method of promoting hydration of mucosal surfaces, comprising administering an effective amount of the compound of Claim 1 to a mucosal surface of a subject.
146. A method of restoring mucosal defense, comprising topically administering an effective amount of the compound of Claim 1 to a mucosal surface of a subject in need thereof.
147. A method of blocking sodium channels, comprising contacting sodium channels with an effective amount of the compound of Claim 1.
148. A method of treating chronic bronchitis, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
149. A method of treating cystic fibrosis, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
150. A method of treating sinusitis, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
151. A method of treating vaginal dryness, comprising administering an effective amount of the compound of Claim 1 to the vaginal tract of a subject in need thereof.
152. A method of treating dry eye, comprising administering an effective amount of the compound of Claim 1 to the eye of a subject in need thereof.
153. A method of promoting ocular hydration, comprising administering an effective amount of the compound of Claim 1 to the eye of a subject.
132
154. A method of promoting corneal hydration, comprising administering an effective amount of the compound of Claim 1 to the eye of a subject.
155. A method of promoting mucus clearance in mucosal surfaces, comprising administering an effective amount of the compound of Claim 1 to a mucosal surface of a subject.
156. A method of treating Sjogren's disease, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
157. A method of treating distal intestinal obstruction syndrome, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
158. A method of treating dry skin, comprising administering an effective amount of the compound of Claim 1 to the skin of a subject in need thereof.
159. A method of treating esophagitis, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
160. A method of treating dry mouth (xerostomia), comprising: administering an effective amount of the compound of Claim 1 to the mouth of a subject in need thereof.
160. A method of treating nasal dehydration, comprising administering an effective amount of the compound of Claim 1 to the nasal passages of a subject in need thereof.
161. The method of Claim 160, wherein the nasal dehydration is brought on by administering dry oxygen to the subject.
162. A method of preventing ventilator-induced pneumonia , comprising administering an effective amount of the compound of Claim 1 to a subject on a ventilator.
133
163. A method of treating asthma, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
164. A method of treating primary ciliary dyskinesia, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
165. A method of treating otitis media, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
166. A method of inducing sputum for diagnostic purposes, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
167. A method of treating chronic obstructive pulmonary disease, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
168. A method of treating emphysema, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
169. A method of treating pneumonia, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
170. A method of treating constipation, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
171. The method of Claim 170, wherein the compound is administered orally or via a suppository or enema.
172. A method of treating chronic diverticulitis, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
173. A method of treating rhinosinusitis, comprising administering an effective amount of the compound of Claim 1 to a subject in need thereof.
134
174. A method of treating hypertension, comprising administering the compound of Claim 1 to a subject in need thereof.
175. A method of reducing blood pressure, comprising administering the compound of Claim 1 to a subject in need thereof.
176. A method of treating edema, comprising administering the compound of Claim 1 to a subject in need thereof.
177. A method of promoting diuresis, comprising administering the compound of Claim 1 to a subject in need thereof.
178. A method of promoting natriuresis, comprising administering the compound of Claim 1 to a subject in need thereof.
179. A method of promoting saluresis, comprising administering the compound of Claim 1 to a subject in need thereof.
135
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